Risk of melanoma in medium-sized congenital melanocytic nevi: a follow-up study

BACKGROUND: The risk of the occurrence of malignant melanoma (MM) in medium-sized (1.5 to 19.9 cm in diameter) congenital melanocytic nevi (CMN) is the subject of controversy. Universally accepted recommendations regarding the management of such lesions have not been made. OBJECTIVE: Our purpose was to assess the risk of MM arising in medium-sized CMN. METHODS: The study included 230 medium-sized CMN in 227 patients, first seen in a private dermatology practice from 1955 to 1996, who were followed up for MM arising within their CMNs. Criteria for entry into the study included (1) a clinically diagnosed medium-sized CMN, (2) minimum follow-up period of 1 year, and (3) a photograph of the lesion in the patient's medical record. RESULTS: No MM occurred in a medium-sized CMN during an average follow-up of 6.7 years (median, 5.8 years) to an average age of 25.5 years (median, 19.1 years). CONCLUSION: The results of this short-term follow-up study do not support the view that there is a clinically significantly increased risk for MM arising in banal-appearing medium-sized CMN or that prophylactic excision of all such lesions is mandatory. Lifelong medical observation seems a reasonable alternative for many medium-sized CMN.     

C-fos protein expression in Spitz nevi, common melanocytic nevi, and malignant melanomas

OBJECTIVE: Neoplastic lesions containing both an adenomatous component and a carcinoid component are rare. To our knowledge, only two such lesions have been reported previously in the large intestine. We report two additional cases to further delineate the histologic features of these lesions and discuss their possible origin. DESIGN: Cases from the surgical pathology files, including consultation material, of the University of Cincinnati (Ohio) were reviewed. PATIENTS: One patient refused repeat colonoscopy at 6 months and subsequently was lost to follow-up. The other patient died 26 months after a hemicolectomy without evidence of recurrence. RESULTS: One lesion represents a collision tumor in which the two histologic components lay adjacent to one another without intermingling. The other is a composite tumor in which the components intermingled in such a way that in some areas the two components were difficult to distinguish from one another. CONCLUSIONS: Although both lesions contain dual components, we believe they are fundamentally different and that they arose from different mechanisms. Definite conclusions regarding prognosis cannot be made owing to the rarity of these lesions; however, there is no evidence to suggest they behave aggressively.     

An unusual presentation of multiple congenital melanocytic nevi with a limb distribution

We report a newborn in whom multiple small congenital melanocytic nevi (MN) were noted on the right side involving the scapular area, shoulder, upper arm and forearm. Such a limb distribution of small congenital MN has never been reported in the literature.     

Syndromes associated with melanocytic nevi

Melanocytic nevi have been reported in association with several congenital syndromes. This review describes the clinical and cutaneous manifestations of six syndromes associated with congenital melanocytic nevi, two associated with acquired nevi, and six associated with melanocytic nevi in which insufficient evidence exists to classify them as congenital or acquired. It is important to recognize these associations to evaluate and counsel patients with melanocytic nevi. Early recognition will also facilitate timely intervention.     

Diagnosing and treating congenital melanocytic nevus simulating malignant melanoma

Many cases reported as malignant melanomas arising in benign congenital melanocytic nevi in the neonatal period have not shown evidence of metastases after several years of follow-up. These lesions were probably pathologically misdiagnosed, thus creating a controversy regarding the precise incidence. This article describes the case of an infant with a giant melanocytic nevus simulating malignant melanoma to illustrate the proper criteria for diagnosis of this condition so extensive and unnecessary therapy procedures can be avoided.     

The augmentation of melanocytic nevi in guinea pigs by solar-simulated light: an animal model for human melanocytic nevi

Strong epidemiological evidence confirms the role of sunlight in human melanoma induction. Furthermore, the frequency of melanocytic nevi is a good indicator of future development of melanoma and a short-term marker of adverse reactions to melanoma-inducing sun exposure in humans. Thus, the aim of this study was to develop and define an animal model for sunlight-induced nevi that can be used as a surrogate model for sunlight-induced melanoma. Five treatment groups of 30-40 Hartley albino guinea pigs/group were treated with topical 7,12-dimethylbenzanthracene at a dose range of 6-240 mg on the dorsum of the skin. At week 20, half of the animals in each group were given a 12-month regimen of minimal erythemal solar-simulated light, 3 times/week, increased weekly to maintain erythema. These regimes induced epidermally derived pigmented melanocytic nevi clinically and histologically similar to human nevi (junctional, compound, and dermal). S100 and HMB45 staining was also consistent with the patterns seen in human nevi. In contrast to the high-dose 7,12-dimethylbenzanthracene-treated animals (60 and 240 mg), where solar-simulated light had no effect on nevi multiplicity, those groups treated with low doses (24, 12, and 6 mg) had a significant increase in nevi multiplicity after 12 months of solar-simulated light treatment (24 mg, 0.5 nevi/animal unirradiated versus 1.4 nevi/animal irradiated, P = 0.03; 12 mg, 0.2 unirradiated versus 1.2 irradiated, P = 0.02; 6 mg, 0 unirradiated versus 1.9 irradiated, P = 0.008). UVB-induced minimal erythemal dose was unaltered after exposure to photoreactivating light, consistent with the observation of others that placental mammals lack the DNA photolyase responsible for strong photoreactivation seen in nonplacental mammals and lower metazoans. Thus, our guinea pig model has some of the essential elements required to be a robust animal model for human nevi and a surrogate model for melanoma. These nevi are augmented by solar-simulated light, are histologically similar, occupy the same level within the skin, have the same natural history as human nevi, and are produced in an animal lacking strong photoreactivation. These features are not found in any previously described small laboratory animal model.     

Pluripotential melanoblastoma, a unifying concept on malignancies arising in congenital melanocytic nevi: report of two cases

Congenital melanocytic nevi are benign lesions present at birth and considered to be caused by a maldevelopment of the neural crest. The malignant potential of the congenital melanocytic nevi have been extensively addressed by several authors, and malignant melanoma is the most frequent neoplasm arising in these lesions. The present report describes two patients with congenital melanocytic nevi in which malignant melanoma with undifferentiated areas showing rhabdomyoblastic differentiation developed. The findings suggest that these mixed neoplasms may be recapitulating the differentiation potential of the ectomesenchyme-neural crest cells. We advocate the term "melanoblastoma" when referring to them.     

Neurocutaneous melanosis: clinical features of large congenital melanocytic nevi in patients with manifest central nervous system melanosis

BACKGROUND: Patients with a large congenital melanocytic nevus (LCMN) may have associated leptomeningeal melanocytosis with or without central nervous system (CNS) melanomas. These patients are considered to have neurocutaneous melanosis, a disorder that, when symptomatic or otherwise manifest neurologically, carries a poor prognosis even in the absence of malignancy. OBJECTIVE: Our purpose was to identify typical clinical features in patients who have manifest CNS melanosis in association with LCMN. METHODS: The records of 117 patients with LCMN in the New York University Registry of LCMN and the reports of 172 cases of LCMN in the world literature were included for features that might signal a high risk for the development of manifest CNS involvement. RESULTS: Of the 289 patients with LCMN, 33 had manifest CNS melanosis. In all 33 in whom symptomatic neurocutaneous melanosis was diagnosed, the LCMNs were present in a posterior axial location on the head, neck, back, and/or buttocks. "Satellite" nevi were known to be present in 31 of the 33 patients. CONCLUSION: Patients with LCMN in a posterior axial location, especially when associated with "satellite" melanocytic nevi, are at greater risk for the development of manifest neurocutaneous melanosis than patients with LCMN limited to the extremities or those who are lacking satellite nevi.     

Interobserver concordance in discriminating clinical atypia of melanocytic nevi, and correlations with histologic atypia

BACKGROUND: The clinical features attributed to atypical (formerly ?dysplastic") nevi and to the atypical multiple mole melanoma syndrome have been used in clinical practice, as well as experimentally, to assign melanoma risk. Little information is available, however, on the interobserver reliability in assessing those features. OBJECTIVE: Our purposes were to quantify interobserver and intraobserver concordances in recognizing certain atypical characteristics of nevi and to correlate the clinical assessments with the histologic characteristics. METHODS: Three observers evaluated clinical photographs of 100 pigmented lesions (predominantly melanocytic nevi, with some lentigines and seborrheic keratoses) from 95 subjects, of whom 85 were family members of four multiple melanoma kindreds and 10 were spouses. Each lesion was rated for border irregularity, color variegation, surface contour irregularity, pigment diffusion, and macularity versus papularity. Predictions were made as to the histologic diagnoses and presence of melanocytic atypia for those lesions judged to be nevi. RESULTS: The pair-wise concordances before agreement on specific criteria were quantified by kappa statistics, which indicated slight to fair agreement in judging the atypical clinical characteristics; concordances increased to moderate levels after consensus development of criteria for color variegation and assessment of macularity, but agreement on the other features remained limited. Whereas macularity and color variegation did correlate somewhat with higher grades of histologic atypia, correlations were generally low between the clinical and histologic diagnoses. CONCLUSION: There is limited interobserver reliability in the clinical assessment of nevus atypia, although correlations do exist between some atypical characteristics and grades of histologic atypia. Because of the low concordances, the clinical discrimination of the melanoma-associated atypical nevus phenotype should rely more on quantitative aspects of the trait, such as total numbers or maximal sizes of nevi, rather than on the subjective determinations of atypia.     

Associated factors in the prevalence of more than 50 common melanocytic nevi, atypical melanocytic nevi, and actinic lentigines: multicenter case-control study of the Central Malignant Melanoma Registry of the German Dermatological Society

Several case-control studies identified common and atypical melanocytic nevi as major risk indicators for the development of cutaneous melanoma. The present investigation was planned to detect factors associated with the prevalence of these melanoma risk markers. Whole-body examination findings and interview data of 513 melanoma patients and 498 age- and sex-matched control subjects were analyzed. Existence of more than 50 common melanocytic nevi and the presence of atypical melanocytic nevi were significantly related to age and gender, with significantly elevated relative risk for their prevalence before the age of 60 and in males. Additionally, sunburns before the age of 20 were significantly associated with both more than 50 common melanocytic nevi (relative risk = 1.7) and the presence of atypical melanocytic nevi (relative risk = 1.5). Actinic lentigines were found more frequently with increasing age, and the presence of actinic lentigines was significantly related to a tendency of freckling in adolescence (relative risk = 2.0) and to two or more sunburns after the age of 20 (relative risk = 1.6). In conclusion, sunburns before the age of 20 contribute to the development of multiple melanocytic nevi and atypical melanocytic nevi. In adulthood, this type of sun exposure is associated with the development of actinic lentigines. The relative risk of developing cutaneous melanoma increases in association with the development of these benign melanocytic lesions.     

Cell lines derived from ultraviolet radiation-induced benign melanocytic nevi in Monodelphis domestica exhibit cytogenetic aneuploidy

The GALT of carp was studied with monoclonal antibodies reacting with carp Ig or carp leukocytes, using (dual) immunofluorescence or immunogold staining on cryosections, cytocentrifuge slides, and cell suspensions of the intestine. The intestinal epithelium contained many Ig-negative lymphoid cells and, in the hindgut, also many large Ig-positive macrophages, which appeared to bind Ig. The lamina propria contained numerous Ig-positive lymphoid cells next to Ig-negative lymphoid cells and granulocytes. Leukocytes isolated from the intestine mainly consisted of Ig-negative lymphoid cells (> 90%). With the methods used, leukocytes were poorly released from the connective tissue. Nevertheless, two types of Ig-containing cells were found: a conventional plasma cell, frequently showing Ig at its surface, and a more common smaller lymphoid cell having a narrow rim of Ig-positive cytoplasm but hardly any Ig on its surface. Many of the Ig-positive lymphoid cells observed in the lamina propria may represent these small Ig-containing cells. Isolated Ig-positive macrophages were frequently associated with B- and T-like cells. Our data strongly suggests an immunological function for the gut of carp, especially for the antigen-transporting hindgut.     

Melanocytic nevi and risk of cutaneous malignant melanoma in southern Spain

The main objective of this study was to assess whether cutaneous malignant melanoma (CMM) shows a stronger relation with the melanocytic nevi count at the site where CMM was diagnosed than with the melanocytic nevi count at other sites, stratifying by histologic CMM type, in a southern Mediterranean population. Cases and controls were selected from a population in southern Spain in 1988-1993. The study population included 116 incident cases with non-familial CMM (International Classification of Diseases 9th Revision (ICD-9) code 172), and 116 controls matched 1:1 for sex and age (+/- 4 years). Data were collected by personal interview, and melanocytic nevi were counted over the entire body surface by clinical skin examination performed by a dermatologist. Crude and multiple risk factor-adjusted odds ratios and 95% confidence intervals were computed by conditional logistic regression analysis. After adjustment by skin type, unexposed skin color, and sun exposure, CMM was found to occur significantly more frequently in individuals with a high number of melanocytic nevi at the same site where CMM originated (odds ratio (OR) for >8 nevi = 12.0, 95% confidence interval (CI) 1.3-108.2). The ability to predict the number of melanocytic nevi on different anatomic sites on CMM, but excluding the CMM cases on each corresponding site, was also examined. A significant trend with the number of nevi on the anterior surface of thighs was found (OR for >4 nevi = 4.5, 95% CI 1.4-14.9). Melanocytic nevi count on the melanoma site was the variable most closely related to superficial spreading melanoma subtype (SSM) (OR for >8 nevi = 82.19, 95% CI 2.72-2,454). On the other hand, the number of melanocytic nevi on the melanoma site was unrelated to risk of CMM subtypes other than SSM. These results support the hypothesis that nevi are an important risk factor for melanoma, especially SSM, in populations with a darker ethnic background.     

Congenital melanocytic nevi and DNA content. An analysis by flow and image cytometry

BACKGROUND: Potential risk factors for the development of melanoma in congenital melanocytic nevi (CMN) are not well established. DNA aneuploidy may constitute such a risk factor but has not been sufficiently studied in CMN. METHODS: In the present study, DNA analysis of eight giant CMN, nine medium CMN (1.5-20 cm), and eight small CMN (< 1.5 cm) was assessed by flow cytometry and selected lesions (six nevi) by DNA image cytometry. DNA content was correlated with patient age, nevus size, and degree of cytologic atypia. RESULTS: DNA aneuploidy was detected by flow cytometry in two giant CMN from adult patients and in a small CMN from a child. DNA aneuploidy was not observed in any of the six CMN studied by image cytometry, although an increased S-phase was noted in a markedly atypical giant CMN. No DNA aneuploidy was detected in medium-sized CMN or in the CMN of nine patients 1 year of age or younger. CONCLUSION: In contrast to previous studies, it was observed that abnormal DNA content does tend to correlate with cytologic atypia, particularly in giant CMN with atypia or melanoma, in adults. Conversely, frank DNA aneuploidy in any CMN in children younger than 1 year of age, irrespective of histologic findings, was not detected. Finally, based on these limited studies, greater sensitivity of image over flow cytometry for detection of DNA aneuploidy cannot be verified.     

Survival and histopathologic characteristics of human melanocytic nevi transplanted to athymic (nude) mice

Melanocytic nevi (n = 406) covering a range of sizes and gross morphologic features were excised from human donors, sampled for histologic diagnosis, and transplanted to athymic (nude) mice. Ninety percent of these xenografts survived transplantation, of which a subset was irradiated daily with ultraviolet light to promote neoplastic transformation. Over 16 weeks of observation, nearly all grafts histologically showed focal inflammatory cell infiltration and fibrosis, progressing in approximately 30% of grafts to complete regression at final observation. During the inflammatory phase, the nevi often had junctional intraepidermal melanocytic hyperplasia in a lentiginous pattern, with cytologic hypertrophy, dendritic morphology, and hypermelaninization. These changes were evident in approximately 20-30% of nevi where they were absent before transplantation, suggesting that host factors, such as those related to the immune response, had stimulated growth. Graft survival was independent of nevus size and initial histologic diagnosis. No melanomas developed in any of the grafts, either spontaneously or with ultraviolet irradiation. These results indicate that successful transplantation can be achieved in a high proportion of human nevus xenografts and that the majority survive for a period of time that would be sufficient for experimental studies. The host response, however, has effects on intraepidermal melanocytic growth that lead to progressive fibrous replacement of the nevus, introducing significant artifacts that compromise the model. Furthermore, malignant transformation of engrafted melanocytes seems to be a rare event, which would limit studies of neoplastic progression in the transplanted melanocytes. Nonetheless, the intraepidermal melanocytic pattern described here evidently constitutes one pattern of melanocyte growth that could be exploited experimentally for studies of growth and differentiation control in melanocytes.     

Adhesion molecule expression in normal skin and melanocytic lesions. Role of UV-irradiation and architectural characteristics in nevi

Cell adhesion between surfaces of cells and to extracellular matrices represents a fundamental mechanism in tissue organization and influences the biological behaviour and the architecture of tumors. We investigated the expression of various adhesion molecules in normal skin (n=5), nevi (n=29), and malignant melanoma (n=10) by immunohistochemistry. Special attention was paid to the correlation between adhesion molecule expression and the respective architectural features, e.g. UV-induced morphological changes, and the arrangement of melanocytes in congenital nevi. In nevi, a single erythemagenic dose of UV-light did not influence the integrin expression of melanocytes, but results in an upregulation of alpha3 beta1- and alpha6 beta1-integrin within the suprabasal layers of the epidermis. This suprabasal labelling was associated with an increased number of suprabasal melanocytes in UV-irradiated nevi which were detected with HMB-45 antibody. Nine of 10 congenital nevi demonstrated a labelling of alpha4 beta1-integrin only in melanocytes of the deeper dermis. This integrin previously has been associated with high tumor thickness and the clinical outcome in melanomas. The integrin profile observed in melanomas differed in part from that seen in nevi with expression of beta2- and beta3-integrins in some cases. The results may indicate a correlation between adhesion molecule expression and histopathological findings in melanocytic lesions.     

Spontaneous malignant transformation of fibrous dysplasia

OBJECTIVE: To evaluate the clinical and radiological findings in diagnosing spontaneous malignant transformation of fibrous dysplasia. METHODS: Fifteen cases of sarcomatous transformation proved by operation and pathological examinations were found in a group of 356 patients with fibrous dysplasia, and their radiological manifestations were retrospectively studied. The 15 cases included 8 osteosarcomas, 5 fibrosarcomas and 2 chondrosarcomas. All the 15 patients were known to have long-standing fibrous dysplasia, but no radiation therapy was ever received. Eleven patients had polyostotic fibrous dysplasia and 4 had monostotic type. RESULTS: Malignant transformation most frequently occurs in the cystic expansive lesion of the long tubular bone. Pains, swelling and late appearance of a bony mass are the main clinical manifestations. The early radiological features of sarcomatous transformation in fibrous dysplasia are moth-eaten or cystic areas of osteolysis located in the involved bone. The cortical destruction and gradual formation of a soft tissue mass that contains tumor-bone are highly suspicious of osteosarcomatous transformation, while ring-like and spotty calcification in the tumor matrix is indicative of chondrosarcoma. Fibrosarcoma usually shows simple osteolytic destruction. CONCLUSIONS: According to the clinical radiological findings, patients of sarcomatous transformation can be detected in the early stage. These radiological findings may be used as a clue for differentiating various kinds of sarcomatous transformation.